Derivatives of xanthine



United States Patent 3,030,363 DERIVATIVES 0F XANTHINE Wilhelm Konz andKarl Zeile, Ingelheim, Germany, as-

signors to C. H. Boehringer Sohn, Ingelheim (Rhine),

Germany, a limited partnership of Germany No Drawing. Filed June 8,1960, Ser. No. 34,648 Claims priority, application Germany June 10, 19596 Claims. (Cl. 260-256) The present invention relates to novelN,N-substituted diamines and various methods of preparing thesecompounds.

More particularly, the present invention relates to compounds having thegeneral structural formulas R and R are selected from the groupconsisting of hydrogen and lower alkyl, preferably with 1 to carbonatoms,

R and R are selected from the group consisting of hydrogen and alkyl,preferably lower alkyl,

X is selected from the group consisting of alkylene with 1 to 12 carbonatoms, lower alkyl-substituted alkylene with 1 to 12 carbon atoms, andcyclohexamethylene, and

Y and Y are selected from the group consisting of Xanthine-yl-( 1Xanthine-yl-(B) Xanthine-yl-(7) 3,7-di-1ower alkyl-xanthine-y1( 1 0lower alkyl lower alkyl 1,7-di-1ower a1ky1-xanthine-yl-( 3 3,030,363Patented Apr. 17, 1962 0 lower alkyl lower alkyl-N and 1,3-di-loweralky1-xanthine-y1-(7) lower alkyl-N l 5 lower alkyl and their non-toxic,pharmacologically useful acid addition salts.

The compounds according to the present invention may be prepared by anumber of diiferent methods. However,

those which have been found to be most advantageous are the following:

(1) By reacting a compound of the formula wherein Y and Y have themeanings defined above and Hal is a halogen, with a diamine of theformulas wherein R R and X have the meanings defined above, at elevatedtemperatures.

In general, one half mol diamine is used for each mol of Compound II or11a in this reaction. The reaction may be carried out with or without asolvent, and the hydrogen halide split 01f by the reaction isneutralized by suitable additives, such as calcium carbonate, sodiumcarbonate, triethylamine or pyridine. Similarly, it is also possible toneutralize the hydrogen halide by using a corresponding excess of thediamine. A preferred embodiment of this process is the operation withouta solvent, wherein one mol of Compound II or IIa is reacted with one molof diamine at temperatures of to 200 C.

Depending upon their properties, the reaction prodnets are isolated bydigestion with water and separation of the desired end products whichare ditficultly soluble in water, or by extraction with a solvent whichis immiscible with water, such as chloroform. In other cases, thereaction products may be isolated by boiling the reaction mixture withalcohol, chloroform etc. Examples of suitable starting materials forthis process are the following: 7-(fi-chlorethy1)-theophy11ine andl-(p-chlorethyl)-theobromine as compounds of the Formula II, andhydrazine, ethylenediamine, trimethylenediamine, tetramethylenediamine,dodecamethylenediamine, N,N'-di* ethyl ethylene-diamine,N,N-diethyl-hexamethylenediamine and piperazine as compounds of theFormula III, 1111: or IIIb.

The present method may also be used to produce those compounds havingthe structural Formulas I, Ia and Ib, which contain two different purineradicals. This embodiment of the reaction is carried out in two steps,for example by first condensing one-half mol of a compound of theFormula II with more than one mol of a diamine of the Formula III, IIIaor IIIb and then reacting the condensation product with one-half mol ofa compound of the Formula IIw wherein Y is difierent from Y in CompoundIII. For example, this method may be used to producehexamethylene-bis-amino-N-(7-ethyl-theophylline N (1 ethyl-theobromine)and trimethylene-bisamino-N-(7-ethyl-theophylline)N'-(7-ethyl-1,3-diethylxanthine).

(2) Condensation of a compound having the structural formulas YCH COR(IV) Y-CH-COR (IVa) wherein Y, Y, R and R have the meanings previouslydefined, with a diamine of the Formula III or IIIa, wherein R and R arehydrogen accompanied by simultaneous hydrogenation. The bis-Schiffsbases may also be produced first and may then be subjected to catalytichydrogenation with or without pressure at room temperature in thepresence or absence of a solvent. For example, under these reactionconditions theophylline-7-acetaldehyde and trimethylenediamine formN,N-bis-(7-ethyltheophylline)-trimethylenediamine, and 7-(fl-oxopropyl)-theophylline and hexamethylenediamine produce N,N- bis-[7-(B-propyl)theophylline]-hexamethylenediamine. Method 2 may also be carried outstepwise to prepare compounds having the Formulas I or Ia in whichradicals Y and Y are diiferent from each other,

(3) Condensation of a compound having the structural formulas wherein Y,Y, R and R have the meanings defined above, with dihalo-alkylenes in thepresence or absence of solvents at elevated temperatures and inthepresence of acid neutralizing agents.

(4) Condensation of a compound having the structural formulas Y-.H (VI)wherein Y and Y have the meanings previously defined, or their alkalimetal salts with a compound having the general formulas wherein R, R, RR and X have the meanings indicated above and Hal is a halogen.

Advantageon-sly, the alkali metal salts of Compounds VI or VIa arereacted in dimethylformarnide as a solvent with. the bis-haloderivatives VII, VIIa or VIIb, in accord-.

wherein Y, Y and R have the meanings defined above, with bis-carbonylcompounds of the general formula R3 R4 0 l 0 (IX) or w R3 R4 0 l-K i 0(Did).

wherein R and R are hydrogen or a lower alkyl radical and X has themeanings defined above; this reaction may be preceded by the formationof the bis-Schiffs base on both sides.

The reaction conditions are the same as those described under method 2.

The present method makes its possible to obtain those compounds havingFormulas I, Ia and 1b in which R and R represent hydrogen. By subsequentalkylation it is also possible to obtain those compounds in which R andR are alkyl radicals.

This process may also be carried out in two steps so that compounds withtwo different radicals Y and Y may be obtained.

(6) Condensation of compounds having the structural formulas an alkali,an alkali metal, an alkali metal amide or cuprous acetate.

This process may also be carried out stepwise so as to obtain compoundsof the Formulas I and Ia with different radicals Y and Y.

(7) By reduction of compounds having the structural wherein R, R, R R Y,Y and X have the meanings previously defined, with a hydrogenatingagent, preferably lithium-aluminum hydride.

The bis-carboxylicacid amideshavingtheab'ove general formulas XI, XIaand XIb are new, but may be produced by customary methods known per se.

The new compounds having Formulas I, Ia and lb may be transferred intotheir acid addition salts in customary 6 heated to 100 C. with 9 partsof ethylenediamine; at this point the exothermic reaction commenced andraised the temperature to 160 C. After cooling to 100 C., the reactionmixture was triturated with'water and the fashion; their monosalts aswell as their bis-salts may be 5 reaction product having the structuralformula EXAMPLE 1 N,N-bis-(7-Ethyl-The0phylline)-Hydrazine A mixture of24.2 parts 7-(18-chloro-ethyl)-theophylline and 5 parts hydrazinehydrate was gradually heated to 100 C.; the reaction mixture, whichbecame homogeneous, was then slowly heated further until the temperaturereached about 120 C. The exothermic reaction which commenced at thispoint caused the temperature to rise to about 145 C. The melt was thenallowed to cool to about 100 C. and thereafter was boiled with 50 wasseparated. Its melting point was 215 to 216 C.; its bis-hydrochloridemelted at 284 C.

EXAMPLE 3 N ,N -Bis-(7-Ethyl-The0phy lline) -Trimethylenediamine 242parts of 7-( 3-chloro-ethyl) theophylline were heated with 78.5 partstrimethylenediamine to a temperature of 80 to 120 C. in a reactionvessel provided with a stirrer, thermometer and cooler. Thereafter, thehomogeneous reaction mixture was stirred without exterior heating,whereby the temperature rose to about 200 C. and the reaction mixturesolidified into a crystalline slurry. The slurry was allowed to cool to120 C. and then about 400 parts boiling water were added, wherebyeverything went into solution. The cooled solution was stirred with 100parts sodium sulfate and the oily precipitate formed thereby was takenup in chloroform. After separation of the chloroform solution thechloroform was evaporated therefrom, leaving behind 205 parts of thereaction product having the structural formula parts water under reflux.After cooling, the snow white reaction product having the structuralformula was separated. The yield was 18.3 parts, which corresponds to83% of theory.

Recrystallized from dimethyl-formamide, the product had a melting pointof 236 to 238 C. Its monohydrobromide had a melting point of 235 C. andwas readil soluble in water.

EXAMPLE 2 N,N-bis-(7-Ethyl-The0phylline)-Ethylenediamine 24.25 parts7-(B-chloro-ethyl)-theophylline were 280 C.

in crystalline form, which corresponds to 84% of theory. Recrystallizedfrom alcohol and dioxan, the product had a melting point of to 188 C.Its bis-hydrochloride had a melting point of 260 to 270 C. (sinteringbeginning at 200 C.).

EXAMPLE 4 N ,N '-B is Z-E thy l-Theophy 1 line) -1TetramethylenediamineN-CH:

were obtained, which represents 96% of theory. The product wastransformed by customary methods into its bis-hydrochloride having amelting point of 276 to 7 EXAMPLE "N,N-Bis-( 7-Ethyl-Theophylline-Pentamethy'lenediamine 'This product was obtained by using a procedureanalogous to that described in Example 4, except thatpentamethylenediamine was used instead of tetramethylenediamine. Thereaction product had the structural formula about of theory.

EXAMPLE 6 N ,N -B is- 7-Ethy l-T h eophy lline) -H txam ethy lenediamine(a) 242.5 parts of 7-(B-chloro-ethyl)-theophylline and 120 partshexamethylenediamine were stirred into a homogeneous melt at 80 to C. ina suitablereaction vessel. creased to about C., accompanied by vigorousstirring, at which point the reaction commenced. With- EXAMPLE '7 N ,N-Bis-(7-Ethyl-The0phylline) -H eptamethylenediamine Using a procedureanalogous to that described in Ex-. After a few minutes the temperaturewas in- '25 ample 4, but substituting heptarnethylenediamine fortetramethylenediamine, a reaction product of the structural formula wasobtained. Its bis-hydrochloride had a melting point of to C.

EXAMPLE 8 N ,N '-Bis-(7-Ethyl-Theophylline) -Octamethylenediamine Usinga procedure analogous to that described in Example 4, but substitutingoctame-thylenediamine for tetra- H; on, O

N-CHr-CHr-HN-(CH r-NH-CHr-C Hr-N N methylenediamine, a reaction producthaving the structural formula were obtained, which corresponds to ayield of 80% of theory. Recrystallized from alcohol, the product had awas obtained; its melting point of 143 to 146 C. Its bis-hydrochloridehad a melting point of 240 to 244 C.

melting point of 170 to 171 C. Its bis-hydrochloride melted at 276 to280 C. and was readily soluble in 70 water. The bis-salt with nicotinicacid, which was also readily water-soluble, had a melting point of 210C. EXAMPLE 9 ('b) 242.5 parts of 7-( 8-chloroethyl)-theophy]line wereheatedin about 1.5 liters methanol with 60 parts N BIS (7 Ethyl g fz ggN Onamethy lene hexamethylenediamine in a stirrer autoclave by slowlyincreasing the temperature to about to C. As 75 Using a procedureanalogous to that of Example 4.

9 10 but substituting nonamethylenediamine fortetramethylmethylenediamine hydrochloride separated out as a enediamine,a reaction product having the structural forwhite precipitate; theprecipitate was separated by vacmula uum filtration and the chloroformwas evaporated from L a; N N CHa-N 0 31-011,

W NCHg-CH:HN(CHz)9-NH-CHr-CHgwas obtained. Its bis-hydrochloride had amelting point the filtrate. The pasty reaction product having thestrucof 196 to 198 C. tural formula 0 2 s H5?! 0 N C gHs-N O O NC 2HN-CHg-CHr-HN-(CHg)oNHCH2CHr-N EXAMPLE 1O 5 was transformed by customarymethods into its his- N,N, Bis (7 Ezhyl Theophyine) Decamethylenehydrochloride having a melting point of 214 to 215 C. diamine EXAMPLE 13Using a procedure analogous to that of Example 4, but N ,N y f rq ine)-Hexamethylenesubstituting decamethylenediarnine for tetramethylenedmmmediamine, a reaction product having the structural formula 12.2 parts of1-(fi-chloro-ethyl)-theobromine were ad 0 CH CH 0 was obtained which,recrystallized from alcohol, had a melting point of 124 to 126 C. Itsbis-hydrochloride mixed with 6 parts hexamethylenediamine and the mixhadameltiflg 1mint of 230 10 ture was homogenized by heating it to 90 to100 0. EXAMPLE 11 Upon slowly increasing the temperature to 130 C. theN,NI B,-S (7 Ethyl The0phyine) D0decamethylene 4 reaction commenced andthe temperature rose to 210 C. diamine The resulting melt was cooled toabout 80 C., admixed Using a procedure analogous to that of Example 4,with about cc. water and heated, and the resulting but substitutingdodeca-methylenediamine for tetr-ameth- Solution was made alkaline withconcentrated sodium Ylenediamine, a reaction 1311x111:t having thesvl'llctllml 50 hydroxide. The reaction product which separated out informula was obtained whose bis-hydrochloride, recrystallized the form ofa viscous oil was isolated by extraction with from a mixture of methanoland ethanol had a melting chloroform. It had the structural formulaP011111 Of 225 to 228 C. CH3 0 0 CH3 EXAMPLE 12 l, l,N,N'-Bis-(7-Ethyl-1,3-Diethyl-Xanthine)- r r -(C a)u-NH-CH Om-N DHexamethylenediamine N A mixture of 5.42 parts of7-(fl-chloro-ethyl)-1,3- diethyl-xanthine and 2.4 partshexamethylenediamine CH5 was carefully melted at C. until homogeneous.Yield: 12.4 parts, which corresponds to 94% of theory. Without furtherexterior heating, the reaction commenced Recrystallized from ethanol byaddition of ether, it had and the temperature rose to about 210 C.Thereafter, a melting point of to 158 C. Its bis-hydrochloride thecrystalline reaction mixture was allowed to cool to had a melting pointof 302 to 305 C. and was readily 90 C. and was then refluxed withchloroform until hexa- 75 soluble in water.

ll 12 EXAMPLE 14 and a melting point of 247 to 248 C. Its bis-hydrochlo-N,N, Diethyl NN, Bl-s (7 Ethyl The0phylline) rrde had a melting point of310 to 312 C.

Ethylenediamine EXAMPLE 17 24.5 parts of7-(,B-chloro-ethyl)-theophylline were 1 h M l heated with 11.6 partsN,N'-diethyl-ethylene-diamine to 5 MN ls[ ropy g si y me] ume fly me 140to 160 C. By boiling the reaction mixture with chloroform, the reactionproduct having the structural A mixture of 59 parts of7-acetonyl-theophyll1ne, 300 formula parts chloroform and 10 partstrimethylenediamine was CH CH Q t I D CHa- O O- N-OH:

\ CzHs C2115 NOH -CHg-N-CHa-CHg-N-OH -CH -N I N rr was isolated and wasthen transformed into its crystalline heated to its boiling point andthe water split off by the bis-hydrochloride. The acid addition salt hada melting reaction was slowly distilled off together with a portionpoint f 172 t 173 C, of the solvent. Thereafter, the reaction solugonwas evaporated in vacuo and the bis-Schifis base aving a EXAMPLE 15melting point of 174 to 176 C. obtained thereby was f i dissolved in 250parts alcohol and 15 parts water. The Hexamethylenedmmme solution wasthen hydrogenated with hydrogen in the 24.5 parts of7-(,B-chloro-ethyl)-theophylline were presence of 0.6 part platinumblack at about 100 C. and heated with 17.2 partsN,N-diethyl-hexamethylenedia pressure of 150 atmospheres gauge. Afterthe theoretamine to 100 to 190 C. and the reaction product was icalamount of hydrogen had been absorbed the catalyst isolated by boilingthe reaction mixture with chloroform. was filtered OE and the virtuallycolorless solution was The initially syruppy reaction product (87% oftheory) evaporated in vacuo. The reaction product having the wastransformed into a crystalline form by treatment with structural formulaCH5 C 5 hot alcohol. The crystalline product had the structural wasobtained with a virtually quantitative yield and was formula thentransformed into its bis-hydrochloride by customary CHa CHB ,1 l

and a melting point of 134 to 136 C. Its bis-hydrochlomeans. Yield: 63.8parts, which corresponds to 87% ride had a melting point of 254 to 255C. of theory. The melting point of the bis-hydrochloride, EXAMPLE 16recrystallized from a mixture of methanol and ethanol,

was 275 C. y p perazine The compounds according to the presentinvention, i.e.

245 parts of 7 (fi chloro ethyl) theophyuine were the disubstituteddiamines represented by Formulas I, heated with gm. piperazine at to TheIa and 112 above and their non-toxic, pharmacologically reaction mixturewas allowed to cool to Q and was acceptable acid addition salts, exhibituseful therapeutic then boiled with 80 cc. alcohol; after cooling, themixture Properties, more Particularly bmncholytic activitifiswas vacuumfiltered and the filter cake was digested with 65 Typical examples ofPharmacologically acceptable, 11011- cold water. The crystallinereaction product had the toxic acid addition salts of the presentdisubstituted distructural formula amines are the monoand bis-additionsalts formed with hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid,valeric acid, oxalic acid, malonic acid, succinic acid, maleic acid,fumaric acid, lactic acid, tartaric acid, citric acid, malic acid,benzoic acid, phthalic acid, cinnamic acid, salicylic acid, nicotinicacid, 2-furoic acid and the like.

While we have illustrated the present invention with the aid of certainrepresentative embodiments thereof, it will be readily apparent to thoseskilled in the art that our invention is not limited to thoseembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. Compounds selected from the group consisting of disubstituteddiamines having a structural formula selected from the group consistingof R and R are selected from the group consisting of hydrogen and alkylwith 1-5 carbon atoms,

R and R are selected from the group consisting of hydrogen and alkyl,

X is selected from the group consisting of alkylene with 1 to 12 carbonatoms, lower alkyl-substituted alkylene with 1 to 12 carbon atoms andcyclohexamethylene, and

Y and Y are selected from the group consisting of and and theirnon-toxic, pharmacologically acceptable acid addition salts.

2. N,N'-bis [,3 (1,3 dimethyl-xanthine-yl-7)-ethyl]- N HN m or N loweralkyl lower alkyl- I lower alkyl trimethylenediamine.

40 3. N,N-bis [6 (1,3 dimethyl-xanthine-yl-7)-ethyl]tetramethylenediamine.

4. N,N'-bis [/3 (1,3 dimethyl-iranthine-yl-7)-ethyl]-hexamethylenediamine.

5. N,N'-bis [B (1,3 dimethyl-xanthine-yl-7 )-ethy1]1octamethylenediamine.

6. N,N-bis 8 (1,3 dimethyl-xanthine-yl-fD-ethyl]- nonamethylenediamine.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N0.3,030,363 April 17, 1962 WilhelmKonz et al.

It is hereby certified that error appears in the above numbered pct entrequiring correction and that the acid Letters Patent should read ascorrected below.

Column 3 line 12, for "Compound III" read Compound 11 column 7, line 19,after the formula in Example 5, insert, its bis-hydrochloride had amelting point of 270 to 272 C. same column 7, in the first line afterthe formula of Example 6 for "80%" read 89% column 9 at the farright-hand side of the formula for Example 9 for "N-CH read l\I--CHSigned and sealed this 14th day of August. 1962.

(SEAL) Atteat:

snuas'r w. swmnn ID L LADD Amazing Officer Commissioner of Patents

1. COMPOUNDS SELECTED FORM THE GROUP CONSISTING OF DISUBSTITUTEDDIAMINES HAVING A STRUCTURAL FORMULA SELECTED FROM THE GROUP CONSISTINGOF